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- What are the common malignancies in patients with Klinefelter’s syndrome?
Patients with Klinefelter’s syndrome are at high risk for the development of
breast cancer, lung cancer, mediastinal germ cell tumors, and non-Hodgkin’s
lymphoma. The risk for breast cancer is increased by 50-fold, while that of
mediastinal germ cell tumors is 500-fold. Although the exact mechanism for
increased cancer risk is not clear, the most likely explanation is overdosage of
genes present in X chromosome which are not lyonized. In addition, abnormal
estradiol/testosterone ratio may also contribute to the development of breast
cancer.- What are the peculiarities of germ cell tumors associated with Klinefelter’s
syndrome?
The most common site of germ cell tumors (GCTs) is gonad in both sexes
(95 %), while the rest are present in mediastinum, retroperitoneum, and central
nervous system. However, in patients with KFS, there are only anecdotal case
reports of testicular GCTs, and the majority of GCTs are present in the anterior
mediastinum. Although the incidence of GCTs is only 1.5 in 1,000 in patients
with KFS, almost 20 % of all mediastinal germ cell tumors are associated with
KFS. GCTs occur much earlier in patients with KFS (childhood and adoles-
cence) as compared to normal population. Children with GCTs classically pres-
ent with precocious puberty along with gynecomastia, whereas adults present
with respiratory symptoms including chest pain, dyspnea, and dry cough. It is
also recommended that patients with mediastinal/intracranial germinoma
should undergo karyotype analysis. High levels of gonadotropins and overdos-
age of genes present in the extra X chromosome have been implicated in the
increased risk of GCTs in patients with KFS. - When to suspect germ cell tumors in a patient with Klinefelter’s syndrome?
Rapid development/worsening of gynecomastia or presence of respiratory
symptoms including chest pain, dyspnea, and dry cough in a patient with KFS
should lead to suspicion of GCTs. In addition, development of precocity in a
child with KFS also merits evaluation for hCG-secreting GCTs. Estimation of
serum β-hCG and alpha-fetoprotein and mediastinal imaging are required to
confirm the diagnosis of GCTs.- When to initiate testosterone therapy in patients with KFS?
Patients with KFS diagnosed during adolescence/adulthood and have low serum
testosterone or have elevated LH (>7.7 IU/L) with normal serum testosterone
should be treated with exogenous testosterone. The rationale for the initiation of
testosterone therapy in those with normal testosterone with elevated LH is to
prevent/delay gonadotropin-mediated testicular damage. However, the benefits
of this approach have not been proven. Patients who are diagnosed to have KFS
during childhood should be monitored with testosterone and LH during puberty7 Delayed Puberty